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Comparative Action of Cardiotonic Steroids on Intracellular Processes in Rat Cortical Neurons
Res Ctr Neurol, Moscow 125367, Russia..
Res Ctr Neurol, Moscow 125367, Russia.;Lomonosov Moscow State Univ, Int Biotechnol Ctr, Moscow 119991, Russia..
Inst Gen Pathol & Pathophysiol, Moscow 125315, Russia..
Lomonosov Moscow State Univ, Int Biotechnol Ctr, Moscow 119991, Russia..
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2018 (English)In: Biochemistry (Moscow), ISSN 0006-2979, E-ISSN 1608-3040, Vol. 83, no 2, p. 140-151Article in journal (Refereed) Published
Abstract [en]

Binding to Na+,K+-ATPase, cardiotonic steroids (CTS) activate intracellular signaling cascades that affect gene expression and regulation of proliferation and apoptosis in cells. Ouabain is the main CTS used for studying these processes. The effects of other CTS on nervous tissue are practically uncharacterized. Previously, we have shown that ouabain affects the activation of mitogen-activated protein kinases (MAP kinases) ERK1/2, p38, and JNK. In this study, we compared the effects of digoxin and bufalin, which belong to different subclasses of CTS, on primary culture of rat cortical cells. We found that CTS toxicity is not directly related to the degree of Na+,K+-ATPase inhibition, and that bufalin and digoxin, like ouabain, are capable of activating ERK1/2 and p38, but with different concentration and time profiles. Unlike bufalin and ouabain, digoxin did not decrease JNK activation after long-term incubation. We concluded that the toxic effect of CTS in concentrations that inhibit less than 80% of Na+,K+-ATPase activity is related to ERK1/2 activation as well as the complex profile of MAP kinase activation. A direct correlation between Na+,K+-ATPase inhibition and the degree of MAP kinase activation is only observed for ERK1/2. The different action of the three CTS on JNK and p38 activation may indicate that it is associated with intracellular signaling cascades triggered by protein-protein interactions between Na+,K+-ATPase and various partner proteins. Activation of MAP kinase pathways by these CTS occurs at concentrations that inhibit Na+,K+-ATPase containing the alpha 1 subunit, suggesting that these signaling cascades are realized via alpha 1. The results show that the signaling processes in neurons caused by CTS can differ not only because of different inhibitory constants for Na+,K+-ATPase.

Place, publisher, year, edition, pages
MAIK NAUKA/INTERPERIODICA/SPRINGER , 2018. Vol. 83, no 2, p. 140-151
Keywords [en]
cardiotonic steroids, digoxin, bufalin, ouabain, Na+, K+-ATPase, primary cultures of neurons, toxicity, MAP kinases, ERK1/2, p38, JNK
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:kth:diva-225317DOI: 10.1134/S0006297918020062ISI: 000426105600006Scopus ID: 2-s2.0-85042566244OAI: oai:DiVA.org:kth-225317DiVA, id: diva2:1195167
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QC 20180404

Available from: 2018-04-04 Created: 2018-04-04 Last updated: 2018-04-04Bibliographically approved

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